New process for the preparation of 2-imino-thiazolidin-4-one derivatives

ABSTRACT

The present invention relates to a new process for the preparation of 2-imino-thiazolidin-4-one compounds of the Formula (I) and (II) and to compounds of Formula (II) as such. The present compounds of Formula (II) can be used as intermediates in the preparation of thiazolidin-4-one derivatives of the General Formula (II), said derivatives being described in WO 2005/054215. These compounds of General Formula (II) are described in WO 2005/054215 to act as immunosuppressive agents.

FIELD OF THE INVENTION

The present invention relates to a new process for the preparation of2-imino-thiazolidin-4-one compounds of the Formula (I) and (II) and tocompounds of Formula (II) as such. The present compounds of Formula (II)can be used as intermediates in the preparation of thiazolidin-4-onederivatives of the General Formula (II), said derivatives beingdescribed in the PCT Patent Application with the publication number WO2005/054215. These compounds of General Formula (II) are described in WO2005/054215 to act as immunosuppressive agents.

DESCRIPTION OF THE INVENTION

In a first aspect the present invention relates to a new process for thepreparation of a compound of the Formula (I):

whereinR¹ represents phenyl which is optionally mono-, di- or tri-substitutedwherein the substituents are independently selected from C₁₋₇alkyl andhalogen; andR² represents C₁₋₇-alkyl;which process comprises reacting a compound of the formula R¹—N═C═S,wherein R¹ is as defined for Formula (I), with a compound of the formulaR²—NH₂, wherein R² is as defined for Formula (I), followed by reactionwith bromo-acetyl bromide and a pyridine base.

Preferably the above process is performed without the isolation and/orpurification of intermediates such as the thiourea intermediate thatoccurs after reacting a compound of Structure 1 with a compound ofStructure 2.

Preferably the pyridine base that is used in the preparation processesdescribed herein is pyridine, lutidine or a cholidine, preferablypyridine.

Preferably the above process is used to prepare compounds of Formula(I), wherein R¹ represents phenyl which is optionally mono-substitutedwith C₁₋₇-alkyl (such as especially methyl) or halogen, and R²represents C₁₋₇-alkyl (such as especially propyl, isopropyl or butyl).

More preferably the above process is used to prepare compounds ofFormula (I), wherein R¹ represents phenyl which is optionallymono-substituted with methyl or chloro, and R² represents propyl,isopropyl or butyl.

Especially preferred, the above process is used to prepare compounds ofFormula (I) selected from the group consisting of:

-   2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-one,-   3-phenyl-2-[(Z)-propylimino]-thiazolidin-4-one,-   2-[(Z)-n-butylimino]-3-phenyl-thiazolidin-4-one,-   2-[(Z)-isopropylimino]-3-o-tolyl-thiazolidin-4-one,-   2-[(Z)-isopropylimino]-3-(3-chlorophenyl)-thiazolidin-4-one, and-   2-[(Z)-propyl imino]-3-o-tolyl-thiazolidin-4-one.

In a further aspect the present invention relates to a process for thepreparation of a compound of Formula (II):

whereinR¹ and R² are as defined for Formula (I) above; andR³ represents hydrogen, hydroxy, C₁₋₇-alkoxy, or halogen;which process comprises preparing a compound of Formula (I) according tothe procedure described above and reacting such compound of Formula (I)with a compound of Structure 3:

wherein R³ is as defined for Formula (II) above.

In a preferred embodiment the present invention relates to a process forthe preparation of a compound of Formula (II) as described above,wherein the compound of Formula (I) is reacted with the compound ofStructure 3 in the presence of acetic acid and a base (especially sodiumacetate), preferably at elevated temperatures, especially attemperatures between 40 and 80° C., preferably at 55° C. The reactioncan also be carried out in a non-polar solvent such as toluene orbenzene in the presence of an amine such as pyrrolidine or piperidine.

In another aspect the present invention relates to a process for thepreparation of a compound of the Formula (II), wherein R¹, R² and R³ areas defined above, which process comprises reacting a compound of theformula R¹—N═C═S, wherein R¹ is as defined for Formula (I), with acompound of the formula R²—NH₂, wherein R² is as defined for Formula(I), followed by reaction with bromo-acetyl bromide and a pyridine base,such as especially pyridine, to obtain a compound of Formula (I)(especially wherein the preparation of the compound of Formula (I)occurs without the isolation and/or purification of intermediates),followed by reaction with a compound of Structure 3, wherein R³ is asdefined above, characterized in that the compound of Formula (I) is notisolated and/or purified, i.e. for example without any extractiveaqueous work-up and concentration to dryness.

In a preferred embodiment the present invention relates to a process forthe preparation of a compound of Formula (II) as described in thepreceding paragraph, wherein the preparation of the compound of Formula(I) occurs in the presence of dichloromethane, followed by a solventchange in order that the reaction with a compound of Structure 3 occursin the solvent acetic acid and in the presence of a base (especiallysodium acetate), preferably at elevated temperatures, especially attemperatures between 40 and 80° C., preferably at 55° C. The reactionwith a compound of Structure 3 can also be carried out in a non-polarsolvent such as toluene or benzene in the presence of an amine such aspyrrolidine or piperidine.

Preferably the above processes are used to prepare compounds of Formula(II), wherein R¹ represents phenyl which is optionally mono-substitutedwith C₁₋₇alkyl (such as especially methyl) or halogen, R² representsC₁₋₇-alkyl (such as especially propyl, isopropyl or butyl), and R³represents hydrogen, C₁₋₇-alkoxy (such as especially methoxy), orhalogen.

More preferably the above processes are used to prepare compounds ofFormula (II), wherein R¹ represents phenyl which is optionallymono-substituted with methyl or chloro, R² represents propyl, isopropylor butyl, and R³ represents hydrogen, methoxy, or chloro.

Especially preferred, the above processes are used to prepare compoundsof Formula (II) selected from the group consisting of:

-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-(o-tolyl)-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropyl    imino]-3-(3-chloro-phenyl)-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-one,-   5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,-   5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propyl    imino]-3-phenyl-thiazolidin-4-one,-   5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,-   5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,-   5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-one,    and-   5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(3-chlorophenyl)-thiazolidin-4-one.

Also especially preferred, the above processes are used to preparecompounds of Formula (II) selected from the group consisting of:

-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-Phenyl-thiazolidin-4-one,-   5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propyl    imino]-3-phenyl-thiazolidin-4-one,-   5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,-   5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,-   5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-(o-tolyl)-thiazolidin-4-one,-   5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-one,    and-   5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propyl    imino]-3-(3-chlorophenyl)-thiazolidin-4-one.

In a further aspect the present invention relates to a compound of theFormula (II), wherein

R¹ represents phenyl which is optionally mono-, di- or tri-substitutedwherein the substituents are independently selected from C₁₋₇-alkyl andhalogen;R² represents C₁₋₇-alkyl; andR³ represents hydrogen, hydroxy, C₁₋₇-alkoxy, or halogen.

In a preferred embodiment, the present invention relates to a compoundof the Formula (II), wherein

R¹ represents phenyl which is optionally mono-substituted withC₁₋₇-alkyl (such as especially methyl) or halogen;R² represents C₁₋₇-alkyl (such as especially propyl, isopropyl orbutyl); andR³ represents hydrogen, C₁₋₇-alkoxy (such as especially methoxy), orhalogen.

In an especially preferred embodiment, the present invention relates toa compound of the Formula (II), wherein R¹ represents phenyl which isoptionally mono-substituted with methyl or chloro, R² represents propyl,isopropyl or butyl, and R³ represents hydrogen, methoxy, or chloro.

In a more specific embodiment, the present invention relates to acompound of Formula (II) selected from the group consisting of:

-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butyl    imino]-3-phenyl-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropyl    imino]-3-(o-tolyl)-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropyl    imino]-3-(3-chloro-phenyl)-thiazolidin-4-one,-   5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propyl    imino]-3-(o-tolyl)-thiazolidin-4-one,-   5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,-   5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propyl    imino]-3-phenyl-thiazolidin-4-one,-   5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,-   5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,-   5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-one,    and-   5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(3-chlorophenyl)-thiazolidin-4-one.

Compounds of Formula (II) described herein can be transformed into thecompounds of General Formula (II) described in the patent application WO2005/054215 using standard methods for the alkylation of phenols, likereaction in a solvent such as ethanol in the presence of a base such assodium hydride, cesium carbonate, potassium carbonate or potassiumtert-butoxide, with an appropriate alkyl halide, alkyl tosylate or alkyltriflate.

Any reference hereinbefore or hereinafter to a compound of Formula (I),Formula (II) or Structure 3 is to be understood as referring also tosalts of such a compound, as appropriate and expedient.

The term C₁₋₇alkyl as used herein means saturated, straight or branchedchain groups with one to seven carbon atoms. C₁₋₇-alkyl as used for R²is preferably n-propyl, isopropyl or n-butyl.

The term C₁₋₇-alkoxy as used herein means an R—O— group, wherein R isC₁₋₇-alkyl.

The term halogen as used herein means fluoro, chloro, bromo or iodo,preferably chloro.

According to the invention, the compounds of Formulae (I) and (II) aremanufactured by the methods given below. In general, they are preparedaccording to the general sequence of reactions outlined below in theGeneral Reaction Scheme.

According to the General Reaction Scheme, compounds of the Formula (II)are prepared following Method B by reacting a compound of Formula (I)with a compound of Structure 3, for instance, in a solvent such asacetic acid at elevated temperatures and in the presence of a base suchas sodium acetate. The required compounds of Formula (I) are preparedfollowing Method A by reacting an isothiocyanate of Structure 1successively with an amine of Structure 2, bromo-acetyl bromide and apyridine base in a solvent such as dichloromethane. Alternatively,compounds of Formula (II) can be prepared following Method C withoutisolating and/or purifying the compounds of Formula (I), such that anisothiocyanate of Structure 1 is reacted successively with an amine ofStructure 2, bromo-acetyl bromide and a pyridine base in a solvent suchas dichloromethane, followed by the addition of an aldehyde of Structure3, for instance, in a solvent such as acetic acid at elevatedtemperatures and in the presence of a base such as sodium acetate. Thecompounds of Structure 1, 2 and 3 are either commercially available orcan be prepared according to procedures known to a person skilled in theart.

EXAMPLES

The following examples illustrate the invention.

All temperatures given are external temperatures and are stated in ° C.Compounds are characterized by ¹H-NMR (400 MHz) or ¹³C-NMR (100 MHz)(Bruker; chemical shifts are given in ppm relative to the solvent used;multiplicities: s=singlet, d=doublet, t=triplet, p=pentuplet, hex=hexet,hept=heptet, m=multiplet, br=broad, coupling constants are given in Hz);by LC-MS (Finnigan Navigator with HP 1100 Binary Pump and DAD, column:4.6×50 mm, Zorbax SB-AQ, 5 μm 120 Å, gradient: 5-95% acetonitrile inwater, 1 min, with 0.04% trifluoroacetic acid, flow: 4.5 mL/min), t_(R)is given in minutes. Melting point is measured on Büchi melting pointapparatus B540 and is not corrected.

ABBREVIATIONS

DMSO dimethylsulfoxideh hour(s)LC-MS liquid chromatography—mass spectrometrymin minute(s)m.p. melting pointt_(R) retention timeTypical Procedure for the Preparation of the 2-imino-thiazolidin-4-onesof Formula (I) (Method A)

To a solution of an arylisothiocyanate of Structure 1 (14.8 mmol) indichloromethane (20 mL) is added portionwise an alkyl amine of Structure2 (14.8 mmol) at 20° C. The solution is stirred at 20° C. for 15 min.The solution is cooled to 0° C. Bromo-acetyl bromide (1.287 mL, 14.8mmol) is added carefully such that the temperature does not rise above5° C. The reaction mixture is stirred at 0° C. for 15 min. To thereaction mixture is added pyridine (2.453 mL, 30.3 mmol) at 0° C. Themixture is stirred for another 15 min. The mixture is warmed to 20° C.The reaction mixture is washed with water (10 mL). The aqueous layer isextracted with dichloromethane (10 mL). The organic layers are combinedand evaporated under reduced pressure to afford a2-imino-thiazolidin-4-one of Formula (I).

Scaffold 1:

2-[(Z)-Isopropylimino]-3-phenyl-thiazolidin-4-one is prepared asdescribed in Method A. LC-MS: t_(R)=0.58 min, [M+1]⁺=235; ¹H-NMR(CDCl₃): δ 7.51-7.47 (m, 2H), 7.43-7.35 (m, 1H), 7.31-7.29 (m, 2H), 3.99(s, 2H), 3.53 (hept, J=6.2 Hz, 1H), 1.15 (d, J=6.2 Hz, 6H); ¹³C-NMR(CDCl₃): δ 171.3, 135.2, 129.0, 128.5, 128.0, 125.8, 53.8, 32.6, 23.2.

Scaffold 2:

3-Phenyl-2-[(Z)-propylimino]-thiazolidin-4-one is prepared as describedin Method A. LC-MS: t_(R)=0.60 min, [M+1]⁺=235; ¹H-NMR (CDCl₃): δ7.51-7.36 (m, 3H), 7.28-7.24 (m, 2H), 3.99 (s, 2H), 3.27 (t, J=7.0 Hz,2H), 1.60 (hex, J=7.0 Hz, 2H), 0.91 (t, J=7.6 Hz, 3H); ¹³C-NMR (CDCl₃):δ 171.3, 135.1, 129.2, 128.7, 128.0, 121.0, 54.2, 32.7, 23.5, 11.8.

Scaffold 3:

2-[(Z)-n-Butylimino]-3-phenyl-thiazolidin-4-one is prepared as describedin Method A. LC-MS: t_(R)=0.69 min, [M+1]⁺=249; ¹H-NMR (CDCl₃): δ7.52-7.48 (m, 2H), 7.44-7.40 (m, 1H), 7.30-7.28 (m, 2H), 4.00 (s, 2H),3.32 (t, J=7.0 Hz, 2H), 1.58 (p, 2H), 1.35 (sex, J₁=7.2, 2H), 0.93 (t,J=7.4 Hz, 3H); ¹³C-NMR (CDCl₃): δ 171.3, 135.1, 129.2, 128.7, 128.0,121.0, 52.2, 32.7, 32.3, 20.5, 13.9.

Scaffold 4:

2-[(Z)-Isopropylimino]-3-o-tolyl-thiazolidin-4-one is obtained followingMethod A. LC-MS: t_(R)=0.67 min, [M+1]⁺=249; ¹H-NMR (CDCl₃): δ 7.35-7.28(m, 3H), 7.15-7.13 (m, 1H), 4.00 (s, 2H), 3.51 (hept, J=6.4 Hz, 1H),2.18 (s, 3H), 1.12 (d, 3H), 1.11 (d, 3H); ¹³C-NMR (CDCl₃): δ 171.1,136.1, 134.6, 131.1, 129.2, 128.6, 126.9, 53.9, 32.6, 23.4, 23.3, 17.6.

Scaffold 5:

2-[(Z)-Isopropylimino]-3-(3-chlorophenyl)-thiazolidin-4-one is preparedas described in Method A. LC-MS: t_(R)=0.76 min, [M+1]⁺=269; ¹H-NMR(CDCl₃): δ 7.43-7.20 (m, 4H), 3.98 (s, 2H), 3.51 (hept, J=6.2 Hz, 1H),1.15 (d, 6H); ¹³C-NMR (CDCl₃): δ 171.0, 136.2, 134.4, 129.9, 128.7,128.5, 126.4, 53.9, 32.5, 23.3.

Scaffold 6:

2-[(Z)-Propylimino]-3-o-tolyl-thiazolidin-4-one is obtained followingMethod A. LC-MS: t_(R)=0.67 min, [M+1]⁺=249; ¹H-NMR (CDCl₃): δ 7.34-7.26(m, 3H), 7.14-7.09 (m, 1H), 4.02 (s, 2H), 3.34-3.22 (m, 2H), 2.20 (s,3H), 1.63-1.54 (m, 2H), 0.90 (t, J=7.4 Hz, 3H); ¹³C-NMR (CDCl₃): δ171.1, 136.1, 134.5, 131.1, 129.4, 128.6, 127.1, 54.4, 32.6, 23.6, 17.6,11.8.

TABLE 1 Summary of the results of the synthesis of the2-imino-thiazolidin- 4-ones of Formula (I) Purity of compound of Ratioof Formula (I) by LC-MS Scaffold Compound Yield [%] isomers^(a)) [area%]^(b)) 1 (I)a 79 95.0:5.0 78.5 2 (I)b 53 91.5:8.5 85.4 3 (I)c 7493.0:7.0 89.0 4 (I)d 73 97.0:3.0 93.6 5 (I)e 77 96.6:3.4 90.1 6 (I)f 7295.5:4.5 85.4 ^(a))Determined by ¹H-NMR ^(b))at 230 nm

The ratio of isomers as given in the above Table 1 refers to the ratioof the major regioisomer of Formula (I) to the minor regioisomer ofFormula (III) as determined by ¹H-NMR.

Typical Procedure for the Knoevenagel Condensation of Compounds ofFormula (I) with Compounds of Structure 3 to Give Compounds of Formula(II) (Method B)

A solution of a 2-imino-thiazolidin-4-one of Formula (I) (4.27 mmol), a4-hydroxy-benzaldehyde of Structure 3 (4.27 mmol) and sodium acetate(700 mg, 8.54 mmol) in acetic acid (10 mL) is stirred at 60° C. for 15h. The suspension is cooled to 20° C. and filtered. The cake on thenutsche is washed with a mixture of water and acetic acid (5 mL, 1/1[v]/[v]). The product is dried under reduced pressure.

Example 1

5-(3-Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-oneis obtained following Method B.

LC-MS: t_(R)=1.02 min, [M+1]⁺=373;

¹H-NMR (deutero DMSO): δ 10.9 (s br, 1H), 7.68-7.65 (m, 2H), 7.52-7.49(m, 3H), 7.45-7.35 (m, 3H), 7.15 (d, J=8.5 Hz, 1H), 3.55 (hept, J=6.2Hz, 1H), 1.10 (d, J=6.2 Hz, 6H);

¹³C-NMR (deutero DMSO): δ 166.0, 155.2, 146.1, 135.9, 132.4, 130.4,129.3, 128.9, 128.8, 126.3, 121.0, 119.1, 117.7, 54.8, 24.0;

m.p.: 270° C.

Example 2

5-(3-Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-oneis obtained following Method B.

LC-MS: t_(R)=1.01 min, [M+1]⁺=373;

¹H-NMR (deutero DMSO): 610.2 (s br, 1H), 7.66 (s, 1H), 7.55-7.48 (m,4H), 7.45-7.41 (m, 1H), 7.37-7.35 (m, 2H), 6.95 (d, J=8.3 Hz, 2H), 3.29(t, J=6.8 Hz, 2H), 1.54 (hex, J=7.3, 2H), 0.86 (t, J=7.3 Hz, 3H);

¹³C-NMR (deutero DMSO): δ 166.1, 155.2, 147.8, 135.9, 132.4, 130.3,129.3, 128.9, 128.8, 126.3, 121.0, 119.2, 117.7, 54.7, 23.8, 12.2;

m.p.: 200° C.

Example 3

5-(3-Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one is obtained following Method B.

LC-MS: t_(R)=1.05 min, [M+1]⁺=387;

¹H-NMR (deutero DMSO): δ 11.0 (s br, 1H), 7.69-7.66 (m, 2H), 7.52-7.48(m, 3H), 7.45-7.41 (m, 1H), 7.37-7.35 (m, 2H), 7.15 (d, J=8.5 Hz, 1H),3.33 (t, J=6.8 Hz, 2H), 1.54-1.46 (m, 2H), 1.34-1.25 (m, 2H), 0.87 (t,J=7.3 Hz, 3H);

¹³C-NMR (deutero DMSO): δ 166.0, 155.4, 147.7, 135.9, 132.5, 130.3,129.4, 128.95, 128.86, 128.2, 126.2, 121.0, 119.1, 117.7, 52.7, 32.7,20.4, 14.2;

m.p.: 192° C.

Example 4

5-(3-Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-(o-tolyl)-thiazolidin-4-oneis obtained following Method B.

LC-MS: t_(R)=1.04 min, [M+1]⁺=387;

¹H-NMR (deutero DMSO): δ 11.0 (s br, 1H), 7.70-7.66 (m, 2H), 7.53-7.51(m, 1H), 7.38-7.25 (m, 4H), 7.15 (d, J=8.3 Hz, 1H), 3.55 (hept, J=6.0Hz, 1H), 2.08 (s, 311), 1.10 (d, J=5.9 Hz, 3H), 1.08 (d, 3H);

¹³C-NMR (deutero DMSO): δ 165.8, 155.3, 145.3, 136.3, 135.2, 132.5,131.1, 130.4, 129.50, 129.46, 129.0, 127.3, 126.2, 121.1, 119.0, 117.7,54.9, 24.1, 24.0, 17.6;

m.p.: 252° C.

Example 5

5-(3-Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-(3-chloro-phenyl)-thiazolidin-4-oneis obtained following Method B.

LC-MS: t_(R)=1.07 min, [M+1]⁺=407;

¹H-NMR (deutero DMSO): δ 11.0 (s br, 1H), 7.68-7.67 (m, 2H), 7.56-7.49(m, 4H), 7.39-7.37 (m, 1H), 7.15 (d, J=8.3 Hz, 1H), 3.55 (hept, J=6.0Hz, 1H), 1.10 (d, J=6.5 Hz, 3H);

¹³C-NMR (deutero DMSO): δ 165.9, 155.5, 145.9, 137.2, 133.3, 132.5,130.9, 130.4, 129.05, 129.01, 128.9, 127.9, 126.1, 121.1, 118.8, 117.8,54.8, 24.0;

m.p.: 272° C.

Example 6

5-(3-Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-oneis obtained following Method B.

LC-MS: t_(R)=1.03 min, [M+1]⁴=387;

¹H-NMR (deutero DMSO): δ 11.0 (s br, 1H), 7.70-7.67 (m, 2H), 7.53-7.51(m, 1H), 7.38-7.25 (m, 4H), 7.15 (d, J=8.3 Hz, 1H), 3.36-3.24 (m, 2H),2.09 (s, 3H), 1.56-1.47 (m, 2H), 0.84 (t, J=7.3 Hz, 3H);

¹³C-NMR (deutero DMSO): δ 165.8, 155.3, 147.0, 136.3, 135.2, 132.5,131.1, 130.3, 129.53, 129.50, 129.0, 127.3, 126.2, 121.1, 119.0, 117.8,54.8, 23.9, 17.6, 12.2;

m.p.: 199° C.

TABLE 2 Summary of the results of the Knoevenagel reactions yieldingcompounds of Formula (II), following Method B Purity of compound ofFormula (II) by LC-MS Example Compound Yield [%] [area %]^(a)) 1 (II)a71 100 2 (II)b 77 100 3 (II)c 84 100 4 (II)d 73 100 5 (II)e 60 100 6(II)f 69 100 ^(a))at 254 nm

Typical One-Pot Procedure for the Preparation of the KnoevenagelProducts of Formula (II) (Method C)

To a solution of an arylisothiocyanate of Structure 1 (14.8 mmol) indichloromethane (20 mL) is added portionwise an alkyl amine of Structure2 (14.8 mmol) at 20° C. The solution is stirred at 20° C. for 15 min.The solution is cooled to 0° C. Bromo-acetyl bromide (1.287 mL, 14.8mmol) is added carefully such that the temperature does not rise above5° C. The reaction mixture is stirred at 0° C. for 15 min. To thereaction mixture is added pyridine (2.453 mL, 30.3 mmol) at 0° C. Themixture is stirred for another 15 min. The mixture is warmed to 20° C.An in-process control is performed to determine the ratio of theregioisomers of Formula (I) and (III). Dichloromethane is removed underreduced pressure. To the residue is added a 4-hydroxy-benzaldehyde ofStructure 3 (14.8 mmol), sodium acetate (2.427 g, 29.6 mmol) and aceticacid (20 mL). The reaction mixture is stirred at 60° C. for 15 h. Thesuspension is cooled to 20° C. and water (20 mL) is added. Thesuspension is filtered. The cake on the nutsche is washed with a mixtureof water and acetic acid (10 mL, 1/1 [ v]/[v]). The product is driedunder reduced pressure.

In an alternative Method C′, the same procedure is followed as describedfor Method C above, except for the following variations: The major partof dichloromethane is removed at ambient pressure at elevatedtemperatures (55-65° C.). Instead of cooling the suspension to 20° C.and adding water after the reaction with the benzaldehyde of Structure3, more solvent is removed under reduced pressure and 75-85° C., andwater (20 mL) is added at 60° C. The suspension is then filtered and thecake on the nutsche is washed with a mixture of water and acetic acid(10 mL), optionally followed by a wash with water (10 mL). The productis then dried under reduced pressure at 20-75° C.

Example 7

5-(3-Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-oneis obtained following Method C.

For analytical data see Example 1.

Example 8

5-(4-Hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-oneis obtained following Method C.

LC-MS: t_(R)=0.93 min, [M+1]⁺=339;

¹H-NMR (deutero DMSO): δ 10.2 (s br, 1H), 7.66 (s, 1H), 7.55-7.48 (m,4H), 7.45-7.41 (m, 1H), 7.37-7.35 (m, 2H), 6.95 (d, J=8.3 Hz, 2H), 3.29(t, J=6.8 Hz, 2H), 1.54 (hex, J=7.3, 2H), 0.86 (t, J=7.3 Hz, 3H);

¹³C-NMR (deutero DMSO): δ 166.3, 159.9, 148.2, 136.0, 132.6, 130.3,129.3, 129.0, 128.8, 125.0, 117.3, 116.8, 54.6, 23.8, 12.2;

m.p.: 232° C.

Example 9

5-(3-Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one is obtained following Method C.

For analytical data see Example 2.

Example 10

5-(4-Hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-oneis obtained following Method C.

LC-MS: t_(R)=0.95 min, [M+1]⁺=369;

¹H-NMR (deutero DMSO): δ 9.84 (s br, 1H), 7.69 (s, 1H), 7.53-7.49 (m,2H), 7.45-7.42 (m, 1H), 7.38-7.36 (m, 2H), 7.26 (s, 1H), 7.16 (d, J=7.8Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.30 (t, J=6.8 Hz, 2H),1.54 (hex, J=7.3, 2H), 0.86 (t, J=7.3 Hz, 3H);

¹³C-NMR (deutero DMSO): δ 166.2, 149.4, 148.4, 135.9, 130.7, 129.4,129.0, 128.8, 125.4, 123.9, 121.0, 117.5, 116.7, 115.1, 56.2, 54.5,23.8, 12.2;

m.p.: 173° C.

Example 11

5-(4-Hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-oneis obtained following Method C.

LC-MS: t_(R)=0.98 min, [M+1]⁺=353;

¹H-NMR (deutero DMSO): δ 10.2 (s br, 1H), 7.67 (s, 1H), 7.55-7.48 (m,4H), 7.44-7.41 (m, 1H), 7.37-7.35 (m, 2H), 6.95 (d, J=8.3 Hz, 2H), 3.33(t, J=6.8 Hz, 2H), 1.54-1.47 (m, 2H), 1.34-1.25 (m, 2H), 0.87 (t, J=7.3Hz, 3H);

¹³C-NMR (deutero DMSO): δ 166.3, 159.9, 148.1, 136.0, 132.6, 130.3,129.3, 129.0, 128.8, 125.0, 117.3, 116.7, 52.7, 32.7, 20.4, 14.2;

m.p.: 228° C.

Example 12

5-(3-Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-Phenyl-thiazolidin-4-oneis obtained following Method C.

For analytical data see Example 3.

Example 13

5-(4-Hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one is obtained following Method C.

LC-MS: t_(R)=0.99 min, [M+1]⁺=383;

¹H-NMR (deutero DMSO): δ 9.86 (s br, 1H), 7.68 (s, 1H), 7.52-7.49 (m,2H), 7.45-7.41 (m, 1H), 7.37-7.35 (m, 2H), 7.26 (s, 1H), 7.15 (d, J=8.3Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.34 (t, J=6.8 Hz, 2H),1.54-1.46 (m, 2H), 1.34-1.25 (m, 2H), 0.87 (t, J=7.3 Hz, 3H);

¹³C-NMR (deutero DMSO): δ 166.2, 149.4, 148.4, 148.1, 136.0, 130.6,129.3, 129.0, 128.8, 125.5, 123.9, 117.5, 116.7, 115.1, 56.2, 52.6,32.6, 20.3, 14.2;

m.p.: 164° C.

Example 14

5-(3-Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-(o-tolyl)-thiazolidin-4-oneis obtained following Method C.

For analytical data see Example 4.

Example 15

5-(4-Hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-oneis obtained following Method C.

LC-MS: t_(R)=0.97 min, [M+1]⁺=353;

¹H-NMR (deutero DMSO): δ 11.1 (s br, 1H), 7.67 (s, 1H), 7.55-7.54 (m,2H), 7.38-7.24 (m, 4H), 6.95 (d, J=8.3 Hz, 2H), 3.36-3.24 (m, 2H), 2.09(s, 3H), 1.56-1.47 (m, 2H), 0.84 (t, J=7.3 Hz, 3H);

¹³C-NMR (deutero DMSO): δ 166.0, 159.9, 147.5, 136.3, 135.3, 132.7,131.1, 130.4, 129.6, 129.4, 127.3, 124.9, 117.2, 116.8, 54.7, 23.9,17.6, 12.2;

m.p.: 198° C.

Example 16

5-(3-Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-oneis obtained following Method C.

For analytical data see Example 6.

Example 17

5-(4-Hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(3-chlorophenyl)-thiazolidin-4-oneis obtained following Method C.

LC-MS: t_(R)=1.02 min, [M+1]⁺=403;

¹H-NMR (deutero DMSO): δ 9.86 (s br, 1H), 7.69 (s, 1H), 7.56-7.50 (m,3H), 7.40-7.37 (m, 1H), 7.26 (s, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.97 (d,J=7.5 Hz, 1H), 3.85 (s, 3H), 3.30 (t, J=6.9 Hz, 2H), 1.59-1.50 (m, 2H),0.87 (t, J=7.4 Hz, 3H);

¹³C-NMR (deutero DMSO): δ 166.0, 149.5, 148.4, 148.0, 137.2, 133.3,130.86, 130.80, 129.1, 128.9, 128.0, 125.4, 123.9, 117.5, 116.7, 115.2,56.2, 54.5, 23.9, 12.2;

m.p.: 200° C.

TABLE 3 Results of the one-pot procedure yielding compounds of Formula(II) following Method C Purity of compound Ratio of isomers of ofFormula (II) Yield intermediates of by LC-MS Example Compound [%]Formula (I) and (III)^(a)) [area %]^(b)) 7 (II)a 88 97:3 100 8 (II)g 8094:6 100 9 (II)b 80 94:6 89.0 10 (II)h 96 93:7 100 11 (II)i 82 94:6 10012 (II)c 86 94:6 97 13 (II)j 84 94:6 76 14 (II)d 83 96:4 100 15 (II)k 7897:3 94 16 (II)f 84 97:3 98 17 (II)l 84 95:5 100 ^(a))Determined byLC-MS at 250 nm after addition of pyridine, prior to the solvent changeto acetic acid. ^(b))at 254 nm

The ratio of isomers as given in the above Table 3 refers to the ratioof the major regioisomer of Formula (I) to the minor regioisomer ofFormula (III), said isomers occurring as intermediates in thepreparation of compounds of Formula (II). The ratio of the isomers isdetermined by LC-MS in an in-process control.

1. A process for the preparation of a compound of the Formula (I):

wherein R¹ represents phenyl which is optionally mono-, di- ortri-substituted wherein the substituents are independently selected fromC₁₋₇alkyl and halogen; and R² represents C₁₋₇-alkyl; which processcomprises reacting a compound of the formula R¹—N═C═S, wherein R¹ is asdefined for Formula (I), with a compound of the formula R²—NH₂, whereinR² is as defined for Formula (I), followed by reaction with bromo-acetylbromide and a pyridine base.
 2. The process according to claim 1,wherein no isolation and/or purification of intermediates occurs.
 3. Theprocess according to claim 1, wherein the pyridine base is pyridine. 4.The process according to claim 1, wherein R¹ represents phenyl which isoptionally mono-substituted with C₁₋₇-alkyl or halogen, and R²represents C₁₋₇-alkyl.
 5. The process according to claim 4, wherein R¹represents phenyl which is optionally mono-substituted with methyl orchloro, and R² represents propyl, isopropyl or butyl.
 6. The processaccording to claim 1 for preparing a compound selected from the groupconsisting of: 2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-one,3-phenyl-2-[(Z)-propylimino]-thiazolidin-4-one,2-[(Z)-n-butylimino]-3-phenyl-thiazolidin-4-one,2-[(Z)-isopropylimino]-3-o-tolyl-thiazolidin-4-one,2-[(Z)-isopropylimino]-3-(3-chlorophenyl)-thiazolidin-4-one, and2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one.
 7. A process for thepreparation of a compound of Formula (II):

wherein R¹ and R² are as defined for Formula (I) in claim 1; and R³represents hydrogen, hydroxy, C₁₋₇-alkoxy, or halogen; which processcomprises preparing a compound of Formula (I) according to the processof any one of claims 1 to 3 and reacting such compound of Formula (I)with a compound of Structure 3:

wherein R³ is as defined for Formula (II) above.
 8. The processaccording to claim 7, wherein the compound of Formula (I) is reactedwith the compound of Structure 3 in the presence of acetic acid and abase, at elevated temperatures.
 9. A process for the preparation of acompound of the Formula (II) according to claim 7, which processcomprises reacting a compound of the formula R¹—N═C═S, wherein R¹ is asdefined for Formula (I) in claim 1, with a compound of the formulaR²—NH₂, wherein R² is as defined for Formula (I) in claim 1, followed byreaction with bromo-acetyl bromide and a pyridine base, to obtain acompound of Formula (I) according to claim 1, followed by reaction witha compound of Structure 3, wherein R³ is as defined in claim 7,characterized in that the compound of Formula (I) is not isolated and/orpurified.
 10. The process according to claim 9, wherein the preparationof the compound of Formula (I) occurs in the presence ofdichloromethane, followed by a solvent change in order that the reactionwith a compound of Structure 3 occurs in the solvent acetic acid and inthe presence of a base, at elevated temperatures.
 11. The processaccording to claim 9, wherein the pyridine base is pyridine.
 12. Theprocess according to claim 7, wherein R¹ represents phenyl which isoptionally mono-substituted with C₁₋₇alkyl or halogen, R² representsC₁₋₇alkyl, and R³ represents hydrogen, C₁₋₇alkoxy, or halogen.
 13. Theprocess according to claim 12, wherein R¹ represents phenyl which isoptionally mono-substituted with methyl or chloro, R² represents propyl,isopropyl or butyl, and R³ represents hydrogen, methoxy, or chloro. 14.The process according to claim 7 for preparing a compound selected fromthe group consisting of:5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-(o-tolyl)-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-(3-chloro-phenyl)-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-one,5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-one,and 5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(3-chlorophenyl)-thiazolidin-4-one.
 15. The processaccording to claim 7 for preparing a compound selected from the groupconsisting of:5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-(o-tolyl)-thiazolidin-4-one,5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-one,and5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(3-chlorophenyl)-thiazolidin-4-one.16. A compound of the Formula (II):

wherein R¹ represents phenyl which is optionally mono-, di- ortri-substituted wherein the substituents are independently selected fromC₁₋₇-alkyl and halogen; R² represents C₁₋₇-alkyl; and R³ representshydrogen, hydroxy, C₁₋₇-alkoxy, or halogen.
 17. A compound according toclaim 16, wherein R¹ represents phenyl which is optionallymono-substituted with C₁₋₇-alkyl or halogen; R² represents C₁₋₇-alkyl;and R³ represents hydrogen, C₁₋₇-alkoxy, or halogen.
 18. A compoundaccording to claim 17, wherein R¹ represents phenyl which is optionallymono-substituted with methyl or chloro, R² represents propyl, isopropylor butyl, and R³ represents hydrogen, methoxy, or chloro.
 19. A compoundaccording to claim 16 selected from the group consisting of:5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-(o-tolyl)-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-(3-chloro-phenyl)-thiazolidin-4-one,5-(3-chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-one,5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-butylimino]-3-phenyl-thiazolidin-4-one,5-(4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(o-tolyl)-thiazolidin-4-one,and5-(4-hydroxy-3-methoxy-benz-(Z)-ylidene)-2-[(Z)-propylimino]-3-(3-chlorophenyl)-thiazolidin-4-one.